Relief from memory dysfunction with α-alkyl-4-amino-3-quinolinemethanols and 1-(4-aralkylamino-3-quinolinyl)alkanones and related compounds

ABSTRACT

There are described compounds of the formula   &lt;IMAGE&gt;   where X is hydrogen, halogen, loweralkyl, loweralkoxy or trifluoromethyl; R is &lt;IMAGE&gt;  R4 being loweralkyl; R1 is hydrogen, loweralkyl or arylloweralkyl; R2 is hydrogen, loweralkyl or arylloweralkyl; and R3 is loweralkyl, with the proviso that when R is acetyl, R3 is methyl and X is hydrogen, R1 and R2 are not both hydrogen, or pharmaceutically acceptable acid addition salts thereof, which are useful for enhancing memory and for treating Alzheimer&#39;s disease.

This is a division of a prior application, Ser. No. 899,585, filed Aug.25, 1986, now U.S. Pat. No. 4,789,678.

There are described compounds of the formula ##STR3## where X ishydrogen, halogen, loweralkyl, loweralkoxy or trifluoromethyl; R is##STR4## R₄ being loweralkyl; R₁ is hydrogen, loweralkyl orarylloweralkyl; R₂ is hydrogen, loweralkyl or arylloweralkyl; and R₃ isloweralkyl, with the proviso that when R is acetyl, R₃ is methyl and Xis hydrogen, R₁ and R₂ are not both hydrogen, or pharmaceuticallyacceptable acid addition salts thereof, which are useful for enhancingmemory and for treating Alzheimer's disease; pharmaceutical compositionscomprising an effective memory enhancing amount of such a compound and amethod of treating a patient in need of memory enhancement whichcomprises administering such a compound to the patient.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1 to 6 carbon atoms. Examples of said loweralkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight- and branched-chain pentyl and hexyl.

The term halogen shall mean fluorine, chlorine, bromine or iodine.

The term aryl shall mean an unsubstituted phenyl group or a phenyl groupsubstituted with 1, 2 or 3 substituent groups each of which beingindependently loweralkyl, halogen, loweralkoxy, or trifluoromethyl.

Throughout the specification and appended claims a given chemicalformula or name shall include all optical isomers and mixtures thereofwhere such isomers exist.

The compounds of this invention are prepared by utilizing one or more ofthe steps described below.

Throughout the description of the synthetic steps, the notations, X, R,R₁, R₂, R₃ and R₄ shall have the respective meanings given above unlessotherwise stated or indicated.

STEP A

Anthranilonitrile is reacted with a diketone of formula II to afford anenamine of formula III> ##STR5##

Said condensation reaction is typically conducted in the presence of asuitable acid catalyst such as p-toluenesulfonic acid and a solvent suchas toluene and refluxing the reaction mixture for several hours.Synthesis of the compound of formula III corresponding to R₃ =R₄ =methylis described in H. Schaefer et al., J. Prakt. Chemie, 321, 695-698(1979). Where R₃ is not the same as R₄, the above reaction gives rise totwo different products, but separation between them can be accomplished,for instance, by flash chromatography.

STEP B

Compound III is cyclized in the presence of sodium methoxide to afford acompound of formula IV. ##STR6##

Said cyclization is typically conducted by first preparing a solution ofsodium methoxide in methanol by a routine procedure and thereafteradding compound III (in neat form or as a methanol solution) to thesodium methoxide solution and gently refluxing the reaction mixture forabout one hour or less. Synthesis of the compound of formula IVcorresponding to R₃ =R₄ =methyl is also described in the above-mentionedSchaefer et al. article.

STEP C

Compound IV is reacted with a bromide compound of the formula R₁ --Br(R₁ is not hydrogen) to afford a compound of formula V. ##STR7##

The above reaction is typically conducted by adding a solution ofcompound IV in a suitable solvent such as dimethylsulfoxide to a slurryprepared from pulverized potassium hydroxide and the same solvent,stirring the resultant mixture at room temperature for less than onehour, adding a solution of the bromide compound in the solvent, andstirring the resultant mixture at room temperature for several hours.

STEP D

Compound V is allowed to react with a bromide compound of the formula R₂--Br (R₂ is not hydrogen) in substantially the same manner as in STEP Cto afford a compound of formula VI. ##STR8##

When R₂ is identical to R₁, it is usually not necessary to conduct STEPD separately from STEP C. Namely, the di N-substituted compound isobtained in the same reaction system along with the mono N-substitutedcompound while conducting STEP C. Separation between the mono and diN-substituted compound can be accomplished, for instance, by flashchromatography using gradient elution of dichloromethane and graduallyincreasing amounts of ethyl acetate.

STEP E

A compound of formula VI where R₁ and R₂ may be hydrogen, loweralkyl orarylloweralkyl which is obtained from STEP C, D or E above is reducedwith sodium borohydride to afford a compound of formula VII. ##STR9##

The above reduction is typically conducted in a suitable medium such asisopropanol, ethanol, methanol or the like and stirring the reactionmixture at a temperature between ambient temperature and refluxtemperature of the reaction mixture.

The compounds of formula (I) of the present invention are useful in thetreatment of various memory dysfunctions characterized by decreasedcholinergic function, such as Alzheimer's disease. This utility isdemonstrated by the ability of these compounds to restorecholinergically deficient memory in the Dark Avoidance Assay.

Dark Avoidance Assay

In this assay mice are tested for their ability to remember anunpleasant stimulus for a period of 24 hours. A mouse is placed in achamber that contains a dark compartment; a strong incandescent lightdrives it to the dark compartment, where an electric shock isadministered through metal plates on the floor. The animal is removedfrom the testing apparatus and tested again, 24 hours later, for theability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animals's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. The results of some of thecompounds of this invention are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                        Dark Avoidance Assay                                                                                    % of Animals With                                                             Scopolamine Induced                                               Dose (mg/kg of                                                                            Memory Deficit                                      Compound      Body Weight)                                                                              Reversed                                            ______________________________________                                        4-amino-α,2-dimethyl-                                                                 2.5         50                                                  3-quinolinemethanol                                                           4-amino-α-ethyl-2-                                                                    1.25        20                                                  methyl-3-quinoline-                                                           methanol                                                                      1-(4-amino-2-methyl-                                                                        0.16        73                                                  3-quinolinyl)propanone                                                        (prior art compounds)                                                         Tacrine       0.63        13                                                  Pilocarpine   1.25        19                                                  ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained: Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

Examples of the compounds of this invention include:

4-amino-α,2-dimethyl-3-quinolinemethanol;

1-(4-benzylamino-2-methyl-3-quinolinyl)-ethanone;

4-benzylamino-α,2-dimethyl-3-quinolinemethanol;

1-[4-(4-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanone;

1-[4-(2-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanone;

1-[4-bis(2-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanone;

1-(4-amino-2-methyl-3-quinolinyl)-propanone;

4-amino-α-ethyl-2-methyl-3-quinolinemethanol;

1-(4-amino-2-ethyl-3-quinolinyl)-ethanone; and

4-benzylamino-α-ethyl-2-methyl-3-quinolinemethanol.

The following examples are given for the purpose of illustrating thisinvention.

EXAMPLE 1 1-(4-Amino-2-methyl-3-quinolinyl)-ethanone

A solution prepared from 11.81 g of anthranilonitrile, 15 g of2,4-pentanedione, about 0.15 g of p-benzenesulfonic acid and 200 ml oftoluene was stirred for 12 hours at reflux, cooled and concentrated togive about 15.5 g of crystals. The crystals were dried in a vacuum ovenat room temperature to give 13.9 g of the desired enamine, m.p. 105° C.,some prior softening.

Sodium metal (0.75 g) was dissolved in 30 ml of anhydrous methanol.After the formation of sodium methoxide, 6 g of the enamine was added tothe solution. After about 45 minutes of gentle reflux, the reactionmixture was cooled, about 2 ml of water was added and most of themethanol was removed by evaporation. The resultant mixture was stirredwith water and extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and concentrated to give 7.5 g of thecyclized product. Recrystallization from benzene gave 4.3 g of a solid.Purification of this material by flash chromatography followed bysublimation gave an analytically pure sample melting at 159°-160° C.

EXAMPLE 2 4-Amino-α,2-dimethyl-3-quinolinemethanol

1-(4-amino-2-methyl-3-quinolinyl)-ethanone (2 g) was added all at onceas a solid to a stirred suspension of sodium borohydride (1.13 g) inisopropanol (50 ml). The mixture was refluxed for several hours untilthe reaction was complete based on thin-layer chromatography (silicagel, 10% methanol/dichloromethane). Methanol (10 ml) and water (5 ml)were added and the mixture was allowed to cool slowly to roomtemperature. Most of the solvent was evaporated under vacuum, and theconcentrate partitioned between water and ethyl acetate. The ethylacetate extract was dried (saturated sodium chloride wash, sodiumsulfate) and the ethyl acetate removed under vacuum. The resulting solidwas recrystallized from acetonitrile to give 1.5 g of crystals, mp 214°.

Analysis:

Calculated for C₁₂ H₁₄ N₂ O: 71.24% C, 6.99% H, 13.85% N,

Found: 71.06% C, 6.87% H, 13.48% N.

EXAMPLE 3 1-(4-Benzylamino-2-methyl-3-quinolinyl)-ethanone hydrochloride

To a solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone (9 g) in 80ml of dimethylsulfoxide was added powdered 85% potassium hydroxide (3.6g). After thirty minutes, benzyl bromide (9 g) was slowly added. Afterfour hours of stirring at ambient temperature, the reaction mixture wasstirred with 80 ml of water and extracted with ether. The organicextract was washed with water and saturated sodium chloride, dried overanhydrous sodium sulfate, filtered and evaporated to 16.4 g of oil. Thisoil was purified by HPLC (high performance liquid chromatography)(silica, 20% ethyl acetate in dichloromethane) to give 5.9 g of thedesired product as a solid, mp 99°-100°. A 2.2 g portion was dissolvedin 25 ml of warm isopropanol, filtered and converted to thehydrochloride salt by the addition of ethereal hydrochloric acid. Thecrystals which formed upon cooling were collected and dried to give 2.2g of solid, d 242°-243°. This material was recrystallized fromethanol/ether to give 2.0 g of crystals, d 242°-243°.

Analysis:

Calculated for C₁₉ H₁₈ N₂ O.HCl: 69.82% C, 5.86% H, 8.57% N,

Found: 69.63% C, 5.99% H, 8.54% N.

EXAMPLE 4 4-Benzylamino-α,2-dimethyl-3-quinolinemethanol

A solution prepared from1-(4-benzylamino-2-methyl-3-quinolinyl)-ethanone (4 g), sodiumborohydride (1 g), 75 ml of isopropanol and 25 ml of methanol wasstirred one hour at 45°, cooled, stirred with 500 ml of water andextracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride and dried over anhydrous sodiumsulfate, filtered and evaporated to 4 g of solid. This material waspurified by flash chromatography (silica, 10% methanol indichloromethane) to give 3.6 g of solid, mp 176°-177°.

Analysis:

Calculated for C₁₉ H₂₀ N₂ O: 78.05% C, 6.90% H, 9.58% N,

Found: 78.11% C, 6.92% H, 9.64% N.

EXAMPLE 51-[4-(4-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanonehydrochloride

A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone (10 g) indimethylsulfoxide (80 ml) was added to a slurry of powdered 85%potassium hydroxide (3.5 g) in dimethylsulfoxide (20 ml). This mixturewas stirred for fifteen minutes, and a solution of 4-fluorobenzylbromide (9.9 g) in dimethylsulfoxide (20 ml) was added dropwise. Afterstirring at ambient temperature for 2.5 hours, the reaction mixture waspoured onto ice/water and extracted with dichloromethane. The organicextract was washed with water, saturated sodium chloride and dried oversodium sulfate. Removal of the sodium sulfate by filtration and thesolvent by evaporation gave 16 g of tacky oil. Approximately 13 g waschromatographed via flash chromatography with ether as eluent to give 5g of pure solid, mp 92°-96°.

The hydrochloride salt was prepared by dissolving 3 g of the solid inabsolute ethanol, adding ethereal/hydrochloric acid and diluting themixture with ether. On stirring at room temperature, a white solidformed which was filtered, washed with absolute ethanol/ether and driedto give 2.7 g of product, mp 222°-224°.

Analysis:

Calculated for C₁₉ H₁₇ FN₂ OHCl: 66.17% C, 5.27% H, 8.12% N

Found: 65.73% C, 5.24% H, 7.98% N.

EXAMPLE 61-[4-(2-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanone

A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone indimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixturewas stirred at ambient temperature for twenty minutes, and thereafter asolution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml)was added dropwise. The mixture was stirred for two hours and allowed tostand overnight at room temperature. Thereafter, it was poured onto iceand diluted with water to form a tacky lump. This was allowed to standfor fifteen minutes, and the aqueous dimethylsulfoxide was decanted. Thetacky precipitate was dissolved in dichloromethane, washed with water(3×) and saturated sodium chloride solution, and dried over sodiumsulfate. Removal of the sodium sulfate by filtration and the solvent byevaporation gave 26.5 g of viscous oil.

Flash chromatography using gradient elution of dichloromethane andgradually increasing amounts of ethyl acetate gave a sufficientseparation to enable the purification and identification of three majorcomponents: the mono, di and tri N-benzylated products. From variousfractions collected, 8.6 g of mono N-benzylated product was isolated.Recrystallization of 4.5 g portion from ether/petroleum ether gave 3.4 gof solid, mp 119°-120°.

Analysis:

Calculated for C₁₉ H₁₇ FN₂ O: 74.00% C, 5.57% H, 9.10% N,

Found: 74.12% C, 5.70% H, 9.12% N.

EXAMPLE 71-[4-bis(2-fluorophenylmethyl)amino-2-methyl-3-quinolinyl]-ethanone

A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone indimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixturewas stirred at ambient temperature for twenty minutes, and thereafter asolution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml)was added dropwise. The mixture was stirred for two hours and allowed tostand overnight at room temperature. Thereafter, it was then poured ontoice and diluted with water to form a tacky lump. This was allowed tostand for fifteen minutes, and the aqueous dimethylsulfoxide wasdecanted. The tacky precipitate was dissolved in dichloromethane, washedwith water (3x) and saturated sodium chloride solution, and dried oversodium sulfate. Removal of the sodium sulfate by filtration and thesolvent by evaporation gave 26.5 g of viscous oil.

Flash chromatography using gradient elution of dichloromethane andgradually increasing amounts of ethyl acetate gave a sufficientseparation to enable the purification and identification of three majorcomponents: the mono, di and tri N-benzylated products. TheN,N-dibenzylated product was obtained as 2.5 g of oil which solidifiedon standing. Recrystallization from ether/petroleum ether gave 1.6 g ofsolid, mp 102°-103°.

Analysis:

Calculated for C₂₆ H₂₂ F₂ N₂ O: 74.97% C, 5.33% H, 6.73% N,

Found: 74.60% C, 5.27% H, 6.68% N.

EXAMPLE 8 1-(4-Amino-2-methyl-3-quinolinyl)-propanone

A solution prepared from anthranilonitrile (26 g), 2.4-hexanedione (25g), 0.2 g of p-toluenesulfonic acid and 400 ml of toluene was stirredfour hours at reflux, cooled and evaporated to 48 g of oil. This oil waspurified by HPLC (silica, dichloromethane) to give 29 g of the majorenamine isomer as an oil.

Sodium metal (3.5 g) was dissolved in 200 ml of methanol. To the freshlyprepared sodium methoxide was added a solution of the enamine (29 g) in100 ml of methanol. After stirring at reflux for thirty minutes, thereaction mixture was cooled, evaporated, stirred with water andextracted with ethyl acetate. The organic extract was washed with waterand saturated sodium chloride, dried over anhydrous sodium sulfate,filtered and evaporated to 27 g of waxy residue. This material waspurified by HPLC (silica, ethyl acetate) to give 18 g of solid, mp130°-133°. A six gram sample was purified by flash chromatography(silica, mp 139°-140°. This material was recrystallized from isopropylether/petroleum ether to give 2.3 g of crystals, mp 140°-141°. Thismaterial was sublimed at 120°-130°/0.01 mmHg to give 2.0 g of crystals,mp 140°-142°.

Analysis:

Calculated for C₁₃ H₁₄ N₂ O: 72.87% C, 6.59% H, 13.08% N

Found: 72.97% C, 6.64% H, 13.25% N.

EXAMPLE 9 4-Amino-α-ethyl-2-methyl-3-quinolinemethanol

A mixture prepared from 1-(4-amino-2-methyl-3-quinolinyl)-propanone (8g), sodium borohydride (3 g), 75 ml of isopropanol and 25 ml of methanolwas stirred twenty hours at ambient temperature. The reaction mixturewas concentrated and stirred with water, and the product which separatedwas collected and dried to 8 g of solid, mp 220°-230°. This material wasrecrystallized from absolute ethanol to give 4.6 g of crystals, mp240°-241°.

Analysis:

Calculated for C₁₃ H₁₆ N₂ O: 72.19% C, 7.46% H, 12.96% N,

Found: 72.04% C, 7.48% H, 12.91% N.

EXAMPLE 10 1-(4-Amino-2-ethyl-3-quinolinyl)-ethanone

A solution prepared from anthranilonitrile (26 g), 2,4-hexanedione (25g), 0.2 g of p-toluenesulfonic acid and 400 ml of toluene was stirredfour hours at reflux, cooled and evaporated to 48 g of oil. This oil waspurified by HPLC (silica, dichloromethane) to give 29 g of the majorenamine isomer as an oil and 1.9 g of the minor enamine isomer as anoil.

Sodium metal (0.25 g) was dissolved in 50 ml of methanol. To the freshlyprepared sodium methoxide was added a solution of the minor enamineisomer (1.8 g) in 10 ml of methanol. After thirty minutes of stirring atreflux, the reaction mixture was cooled, evaporated, stirred with waterand extracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride, dried over anhydrous sodiumsulfate, filtered and evaporated to 1.6 g of solid. This material waspurified by flash chromatography (silica, 50% ethylacetate/dichloromethane) to give 1.1 g of solid, mp 145°-148°. A 200 mgsample was sublimed at 135°-145°/0.01 mmHg to give 150 mg of crystals,mp 148°-150°.

Analysis:

Calculated for C₁₃ H₁₄ N₂ O: 72.87% C, 6.59% H, 13.08% N,

Found: 72.87% C, 6.66% H, 13.10% N.

We claim:
 1. A method of treating a patient in need of relief frommemory dysfunction characterized by decreased cholinergic function,which comprises administering to the patient an effective amount of acompound having the formula ##STR10## where X is hydrogen, halogen,loweralkyl, loweralkoxy or trifluoromethyl; R is ##STR11## R₄ beingloweralkyl; R₁ is hydrogen, loweralkyl or arylloweralkyl; R₂ ishydrogen, loweralkyl or arylloweralkyl; and R₃ is loweralkyl, with theproviso that when R is acetyl, R₃ is methyl and X is hydrogen, R₁ and R₂are not both hydrogen, or a pharmaceutically acceptable acid additionsalt thereof.